Benzene-sulfonyl ureas



United States Patent 1m. or. C07c 11 7/00, 143/38 US. Cl. 260-553 4Claims ABSTRACT OF THE DISCLOSURE Highly effective antidiabetic agentscomprising benzenesulfonyl ureas and the alkali metal salts thereofwherein the free compound corresponds to the formula:

wherein A is an aliphatic, cycloaliphatic, aryl, aralkyl, aralkoxyalkylor heterocyclic radical, X is a divalent aliphatic radical and R is analiphatic or cycloaliphatic radical (which can be interrupted by oxygenor sulfur atoms) an aryl or aralkyl radical.

This invention relates to new therapeutic compositions havingantidiabetic activity. More particularly, the invention relates tocertain benzene-sulfonyl ureas having antidiabetic properties and to thepreparation of such com pounds and the formulation thereof astherapeutically useful compositions.

It is known that various benzene-sulfonyl ureas possess blood sugardecreasing activity and are suitable for use as oral administrableantidiabetic agents (cf., for example, Arzneimittel-Forschung, 8,448-454/ 1958). In particular, N -sulfani1yl-N -(n-butyl)-urea and N-(4-methylbenzene-sulfonyl)-N -(n-butyl)-urea have achieved greatimoortance in diabetes therapy.

The active antidiabetic agents in accordance with the present inventioncan be identified as benzene-sulfonyl ureas of the formula wherein A isan unsubstituted or substituted, or straight or branched chain,saturated or unsaturated, aliphatic or cycloaliphatic radical, anunsubstituted or substituted, aryl, aralkyl, or aryloxyalkyl radical ora heterocyclic radical; X is a straight or branched chain, saturated orunsaturated divalent aliphatic radical; and R is a straight or branchedchain, saturated or unsaturated aliphatic or cycloaliphatic radical,which may be interrupted by oxygen or sulphur atoms or an unsubstitutedor substituted aryl or aralkyl radical.

These compounds possess surprisingly strong blood sugar reducingactivity. This degree of activity appears to be unique with theforegoing compounds and is not found in even quite closely relatedbenzene-sulfonyl ureas.

The active compounds of the present invention can be prepared by thevarious methods known for the synthesis ICC of substituted ureas. Somepresently preferred procedures are hereinafter set out:

(21) Reaction of a benzene-sulfonyl compound of the formula:

with a compound of the formula UR, wherein A, X, and R are as above, oneof the substituents Z and U is an amino group and the other is anisocyanate group or a substituent converted into an isocyanate groupunder the reaction conditions.

Thus, for example, a sulfonyl isocyanate is reacted with an amine of theformula R-NH wherein R is as above, or with an acyl derivative thereofor, alternatively, a sulfonamide, advantageously in the form of itssodium or potassium salt, is condensed with an isocyanate of the formulaRNCO, wherein R is as above. In place of the isocyanates, there can alsobe used those compounds which, under the reaction conditions, arecapable of conversion into an isocyanic acid ester. As isocyanateformers of this type, there can be used, for example, carbamic acidhalides, urethanes, thiourethanes, ureas, acyl derivatives of ureas, anddisulfonyl ureas;

(b) Hydrolysis of benzene-sulfonyl thioureas of the formula:

wherein A, R, and X are as above, or of benzene-sulfon guanidines of theformula:

wherein A, R, and X are as above, or of benzene-sulfonylisourea ethersof the formula:

wherein A, R, and X are as above;

(c) Reaction of benzene-sulfonyl halides of the formula:

wherein A and X are as above and Hal is a halogen atom, with ureas ofthe formula H N-CONHR, wherein R is as above defined. In this procedure,in place of the ureas there can also be used the corresponding parabanicacid derivatives of the formula:

in which R is as above.

3 In the above-mentioned syntheses, the moiety A-COX- can also first beintroduced into the final sulfonyl ureas. The following are reactionsfor this purpose:

In the above formulas, A, R, X, and Hal are as above defined.

The novel benzene sulfonyl urea compounds of this invention can beconverted into their alkali metal, alkaline earth metal or ammoniumsalts in the conventional manner. Thus, for example, the alkali metalsalts of the benzene sulfonyl urea compounds of this invention can beprepared by dissolving the selected compound in an aqueous or alcoholicsolution of the alkali metal hydroxide and, if desired, isolating thesalt by evaporating the solvent. Any of the conventional alkali metalsalts such as the sodium, potassium, lithium, or the like salts, can beprepared by this method or by other methods known to organic chemists.

The benzene-sulfonyl urea compounds of this invention, as well as thecorresponding alkali, alkaline earth metal, and ammonium salts are newcompounds, and both of these series of compounds have a surprisinglyhigh order of antidiabetic activity.

The preparation of these compounds is more fully described in thefollowing examples. It is to be understood, however, that the examplesare illustrative of the compounds embraced by this invention and of themethods for their preparation, and are not to be construed as limitingthe invention to the particular compounds or methods specificallydescribed.

EXAMPLE 1 N [p- (p-benzoyl-ethyl)-benzene-sulfonyl]-N cyclohexyl-urea 8g. cyclohexyl isocyanate were added dropwise, over a period of 1 hourand at about a temperature of +10 C., to 11.5 g. p-(B-benzoyl-ethyl)benzene-sulfonamide which had previously been dissolved in 20 ml. 2 Nsodium hydroxide solution, 100 ml. water and 100 ml. acetone. Theresulting reaction mixture was kept at room temperature for 1 hour. Anyundissolved material was filtered ofi? and dilute hydrochloric acid wasthen added to the filtrate until a pH of 8.1 was obtained. Following afurther addition of dilute hydrochloric acid, the crystalline slurrywhich separated was filtered off with suction. The yield amounted to 4.6g. (28.5% of theory). After recrystallization from methanol, the N -[p-(fi-benzoyl-ethyD-benzone-sulfonyl]-N -cyclohexyl urea which was obtainedmelted at 184-185 C.

The p-(fi-benzoyl-ethyl)-benzene-sulfonamide required as startingmaterial can be prepared in the following manner:

p-Nitrobenzaldehyde was first condensed with acetophenone producingS-benzoyl-p-nitrostyrene (M.P. 163- 164 C.; yield 80% of theory). The,B-benzoyl-p-nitrostyrene was reduced with stannous chloride andhydrochloric acid producing B-benzoyl-p-aminostyrene (M.P. 153-154 C.;yield 71.5% of theory) which was diazotized using the Meerwein-Sandmeyermethod. The crude p-(fi-benzoyl-vinyl)-benzene-sulfonyl chloride soobtained (M.P. 146148 C.; yield 48% of theory) was reacted with ammoniawhereby the corresponding sulfonamide (M.P. 186-188 C.; yield of theory)was obtained. The latter was dissolved in dilute sodium hydroxidesolution and methanol and partially hydrogenated at room temperature inthe presence of a palladium-barium sulfate catalyst producing thep-(B-benzoyl-ethyl)-benzenesulfonamide (M.P. 154-156 C.; yield 75% oftheory).

EXAMPLE 2 N;- [p- ('y-beuzioyhpropyl -benzene-sulfonyl] -Ncyclohexyl-urea 13.5 g. p-(v-benzoyl-propyl)-benzene-sulfonamide, weredissolved in 500 ml. acetone, 150 ml. water and 70 ml. 1 N sodiumhydroxide solution, and thereafter reacted, in the manner described inExample 1, with 8.2 g. cyclohexyl isocyanate. The resulting reactionmixture was further Worked up as set out in Example 1. There wereobtained 5.7 g. (30% of theory) N [p-('y-benzoyl-propyl)-benzene-sulfonyl]-N -cyclohexyl-urea having a melting point of ll81 C.(recrystallized from methanol).

The p- ('y-benzoyl-propyl -benzene-sulfonamide required as startingmaterial can be prepared in the following manner:

fi-Nitrophenyl-ethyl bromide which had been obtained by the nitration of,B-phenyl-ethyl bromide, was reacted with sodium malonic acid diethylester to give p-nitrophenyl-ethyl-malonic acid diethyl ester and thelatter then saponified and decarboxylated producing'y-(p-nitrophenyl)-butyric acid (M.P. 92 C.; yield 50% of theory).Following treatment of the 'y-p-nitrophenyD-butyric acid with thionylchloride, there was obtained the corresponding acid chloride (B.P.168l71 C./0.4 mm. Hg) which was subjected to a Friedel-Crafts reactionwith benzene and aluminum chloride, to producea-(p-nitro-phenylethyl)-acetophenone (M.P. 109-110 C.; yield 78% oftheory). This nitro-ketone was then reduced with stannous chloride andalcoholic hydrochloric acid whereby the a-(p-aminophenyl-ethyl)-acetophenone was obtained (M.P. 6668 C.; yield83.5% of theory). The flp-aminophenyl-ethyl)-acetophenone was diazotizedby the Meerwein- Sandmeyer method and the resultant crude sulfonylchloride thereafter reacted with ammonia to givep-(y-benzoyl-propyl)-benZene-sulfonamide (M.P. 196l97 C.; yield 67% oftheory).

EXAMPLE 3 N [4- (butan-3'-on- '-yl)-benzene-su1fonyl]-N cyclohexyl-urea15.1 g. 4-(butan-3'-on-1-yl)-benzene-sulfonamide were dissolved in 33.5ml. 2 N sodium hydroxide solution and 70 ml. acetone and thereaftermixed dropwise, with stirring and at 0-5 C., with 8.4 g. cyclohexylisocyanate. The reaction mixture was further stirred for 3 hours anddiluted with water. Any undissolved material present was separated offby filtering and the filtrate acidified. The N [4 butan 3' on 1' yl)benzene sulfonyl] -N cyclohexyl-urea which was thereby obtained in theform of crystals melted, after recrystallization from methanol, at -126C.

The following compounds were obtained in an analogous manner:

N [4 (butan-3'-on-1'-yl) benzene-sulfonyl] N butyl-urea having a meltingpoint of 99-100 C. (recrystallized from methanol);

N [4 (butan-3'-on-1-yl) benzene-sulfonyl] N cyclo-octyl-urea having amelting point of 87-88" C. (recrystallized from methanol); and

N [4 (butan-3'-on-1-yl) benzene-sulfonyl] N (4-methyl-cyclohexyl)-ureahaving a melting point of 122-123 C. (recrystallized from methanol).

The 4-(butan-3'-on-1-yl)-benzene-sulfonamide. required as startingmaterial was prepared in the following manner:

172 g. p-amino-benzene-sulfonamide were diazotized in the conventionalmanner in 240 ml. concentrated hydrochloric acid and 1 liter water witha solution of 69 g. sodium nitrite in 400 ml. water. The diazoniumsolution was thereafter mixed with 500 ml. acetone and 92 g. methylvinyl ketone and also gradually, in small portions, with 50 g. cuprouschloride. A vigorous evolution of nitrogen set in and the temperature ofthe reaction mixture rose to almost 40 C. The reaction mixture wasstirred for a further 20 minutes. The resultant oil was 4-(2-chlorobutan-3-on-1'-yl)-benzene-sulfonamide which was further worked upwithout purification. All of the crude product was dissolved in 700 ml.glacial acetic acid and mixed portion-wise with 250 g. zinc dust. Thereaction mixture was heated on a steam bath for 2 hours, filtered usingsuction and the filtrate evaporated. The residue crystallized followingmixting the water. The crystals were filtered off with suction andrecrystallized'from methanol. The4-(butan-3'-on-l-yl)-benzene-sulfonamide was obtained in good yield andmelted at 94-96 C.

EXAMPLE 4 N1- [p B-benzoyl-butyD -benzene-sulfonyl] -N cyclohexyl-ureaThere were obtained by reaction of 12.6 g.p(5-benzoylbutyl)-benzene-sulfonamide, dissolved in 140 ml. acetone, 70ml. water and 20 m1. 2 N sodium hydroxide solution and 6 g.cyclohexyl-isocyanate followed by the conventional working up, 4.4 g.(28% of theory) N [p-(fibenzoyl-butyl -benzene-sulfonyl] -N-cyclohexyl-urea having a melting point 154-156" C.

The p-(e-benzoyl-butyl)-benzene-sulfonamide required as startingmaterial was prepared as follows:

p-Nitro-cinnamyl aldehyde and acetophenone were first condensed in theconventional manner and the reaction product (M.P. l68-l70 yield 40% oftheory) hydrogenated at room temperature in glacial acetic acid in thepresence of a palladium-barium sulfate catalyst producingp-(a-benzoyl-butyl)-aniline (M.P. 7071 0.; yield 50% of theory). Thisp-(6-benzoyl-butyl)-aniline was subjected to a Meerwein-Sandmeyerreaction, whereby p-(fi-benzoylbutyl) benzene=sulfonamide (M.P. 1l61l80.; yield 58% of theory) was obtained.

EXAMPLE 6 g. (p-(y-benzoyl-propyl)-benzene-sulfony1 ethyl urethane(prepared from p-(y-benzoyl-propyl)-benzene-sulfonamide and ethylchloroformate in acetone in the presence of potassium carbonate; M.P.116-118 C.; yield 63% of theory) and 2.1 g. 4-methoxy-cyclohexy1- aminewere heated with 6 ml. dimethyl formamide for 1 hour at 100 C. and for/2 hour at 120 C. (oil bath) and thereafter stirred into 150 ml. water.The separated crystalline slurry which formed was filtered oil withsuction, Washed with water and dried. There were obtained 6.6 g. (90% oftheory) N [p-('y-benzoyl-propyl)-benzenesulfonyl] -N-(4-methoxy-cyclohexyl)-urea having a melting point of 130-131 C.(recrystallized from methanol).

The following compounds were obtained using an analogous procedure:

N [p -benzoyl-propyl)-benzene-sulfonyl]-N -(4- rnethyl-cyclOhexyD-urea;yield 96% of theory; M.P. 17 6- 177 C. (recrystallized from methanol);

N [p ('y-benzoyl-propyl)-benzene-sulfony1]-N -(4- 6ethyl-cyclohexyl)-urea; yield 81% of theory; M.P. 154- 156 C.(recrystallized from methanol); and

N [p -benzoyl-propyl)-benzene-sulfonyl]-N -cyclooctyl-urea; yield 73% oftheory; M.P. 124125 C. (recrystallized from methanol).

EXAMPLE 6 N p- [7- (p-chlorobenzoyl) -propyl] '-benzene-sulfonyl}- N-cyclohexyburea 5 .5 g. p- ['y- (p-chlorobenzoyl -propyl]-benzene-sulfonylethyl urethane (M.P. 137139 C. which had been preparedin a yield amounting to 78% of theory by a procedure analogous to thatused for the production of p-(vbenzoyl-propyl) benzene sulfonyl-ethylurethane) and 1.35 g. cyclohexylamine were reacted in 5 ml. dimethylformamide and the reaction mixture Worked up. There were obtained 4.6 g.(74% of theory) N -{p- ['y-(p-chlorobenzoyl) propyl] benzene sulfony1}-N-cyclohexylurea having a melting point of 172-173 C. (recrystallizedfrom methanol).

In an analogous manner there was obtained N -{p-[y- (p-chlorobenzoyl)propyl] benzene-sulfonylf -N lmethyl-cyclohexyD-urea; yield 53% oftheory; M.P. 168- 169 C. (recrystallized from methanol).

The p ['y-(p-chlorobenzoyl)-propyl]-benzene-sulfonamide required asstarting material was prepared in the following manner:

Chlorobenzene and p-nitrophenyl-butyric acid chloride were first reactedin a Friedel-Crafts reaction to give p['y-(p-chlorobenzoyl)-propyl]-nitroben2ene (M.P. 82-84 C.; yield 54% oftheory), the nitro group of which was reduced with stannous chloride andalcoholic hydrochloric acid to give the corresponding amine (M.P. 114116C.; yield 78% of theory) which was then converted into the correspondingsulfonyl chloride by a Meerwein-Sandmeyer reaction and the sulfonylchloride then reacted with ammonia to give the desired sulfonamide (M.P.154- 156 C.; yield 67% of theory).

EXAMPLE 7 N -[p-('y-benzoyl-propyl)-benzene-sulfonyl]-N -(4- isopro poxy-cyclohexyl) -urea 4.3 g. p ('y benzoylpropyl)-benzene-sulfonyl-ethyl urethane were heated under reflux for 1%hours with 1.8 g. 4 isopropoxy cyclohexylamine in ml. toluene. Aftercooling, the clear solution was extracted twice with 75 ml. amounts of0.5 N sodium hydroxide solution. The aqueous solution was clarified byshaking out with ether and adjusted to pH 6 with dilute hydrochloricacid. The snlfonyl-urea, which was thereby separated out in the form ofcrystals, was filtered off with suction, washed with water, dried in avacuum and recrystallized from methanol. Yield 65% of theory; MJP.1l8120 C.

The following compounds were obtained in an analogous manner:

N [p-(' -benzoyl-propyl)-benzene-sulfonyl]-N -n-butyl-urea by thereaction of 11.2 g. p('y-benzoy1-propyl)- benzene-sulfonyl-ethylurethane with 2.2 g. n-butylamine;

yield 88% of theory; M.P. 136137' C. (recrystallized EXAMPLE 8 N p-(fl-benzoyl-vinyl -benzene-sulfony1] -N cyclohexyl-urea This compoundwas prepared by a method analogous to that described in Example 7, bythe reaction of 10.8 g. p-(fl-benzoyl-vinyl)-benzene-sulfonyl-ethylurethane with 3 g. cyclohexylamine. Yield 79% of theory; M.P. 202 C.(recrystallized from aqueous acetone).

In an analogous manner, there was obtained, using 3.4 g. trans 4methyl-cyclohexylamine, N -[p-(fl-benzoyh vinyl) benzene sulfonyl] N-(4-methyl-cyclohexyl)- urea; yield 78% of theory; M.P. 221-222 C.(recrystallized from alcohol-acetone (1:1)).

The sulfonyl urethane used as starting material was obtained by reactingp-(fi-benzoyl-vinyl)-benzene-sulfonamide and ethyl chloroformate inacetone in the presence of potassium carbonate; M.P. 180181 C.; yield43% of theory.

EXAMPLE 9 N [p- ('y-benzoyl-propyl)-benzene-sulfonyl]-N (tetrahydrothiapyr anyl-4) -urea N -[p ('y benzoyl-propyl) benzene sulfonyl]-N(tetrahydrothiapyranyl-4)-urea was prepared by a method substantially asdescribed in Example 5, by the reaction of 11.2 g.p-('y-benzoyl-propyl)-benzene-sulfonyl ethyl urethane with 3.5 g.4-amino-tetrahydrothiapyran in 11 ml. dimethyl formamide. Yield 69% oftheory; M.P. 217 C.

EXAMPLE 1O N -[p-(y-p-toluyl-propyl)-benzene-sulfonyl]-N-cyclohexyl-urea The preparation of N -[p-(y-p-toluylpropyl)-benzene-sulfonyl]-N -cyclohexyl-urea was carried out by a methodanalogous to that described in Example 5, by the reaction of 4.3 g.p-('y-p-toluyl-propyl)-benzene-sulfonylethyl-urethane with 1.1 g.cyclohexylamine in 4 ml. dimethyl formamide. Yield 84% of theory; M.P.191 C. (recrystallized from methanol).

In an analogous manner, there was obtained, using 1.2 g.trans-4-methyl-cyclohexylamine, N -[p ('yptoluylpropyl)-benzene-sulfonyl]-N -(4 methyl cyclohexyl)- urea; yield72% of theory; M.P. ISO-181 C. (recrystallized from methanol).

The sulfonyl urethane used as starting material was prepared as follows:

Toluene and p-nitrophenyl-butyric acid chloride were first reacted by aFriedel-Crafts reaction producing p-(y-ptoluyl-propyl)-nitrobenzene(M.P. 8586 C.; yield 53% of theory). The nitro group of thep-(y-p-toluyl-propyD- nitrobenzene was reduced with stannous chloride inalcoholic hydrochloric acid giving the corresponding amino compound(yield 82% of theory; M.P. 108l09 C.). The corresponding sulfonylchloride was prepared therefrom by a Meerwein-Sandmeyer reaction (M.P.78-80 C.) and this compound was converted with ammonia into p('y-toluyl-propyl)-benzene-su1fonamide (yield 64% of theory; M.P.183-184 C.). From this sulfonamide there was obtained the correspondingsulfonyl-urethane by reaction with ethyl chloroformate in acetone in thepresence of potassium carbonate (yield 50%; M.P. 126128 C.).

EXAMPLE l1 N -[p-('y-o-methoxy-benzoyl-propyl)-benzene-sulfonyl]- N-cyclohexyl-urea 5.5 g. p-(y-o-methoxy-benzoyl-propyl) benzene-sulfonyl-ethyl urethane (prepared fromp-(y-o-methoxy-benzenoyl-propyl)benzene-sulfonamide and ethylchloroformate in acetone in the presence of potassium carbonate, M.P.132133 C.; yield 71% of theory) in 100 ml. toluene and 20 ml. dimethylformamide were mixed with 1.36 g. cyclohexylamine and the clear solutionobtained gently boiled for 1 hour. After cooling, the reaction mixturewas stirred with 60 ml. Water and the crystalline product whichseparated out filtered 01f with suction. It was washed with water anddried in a vacuum. After recrystallization from methanol, there wereobtained 5.2 g. (84% of theory) N-[p-('y-o-rnethoxy-benzoyl-propyl)-benzenesulfonyl]-N -cyclohexyl-ureahaving a melting point of 191192 C.

8 EXAMPLE 12 N [p- 'y-fl-naphthoyl-propyl -benzene-sulfonyl] -Ncyclohexyl-urea 10 g. p-('y-B-naphthoyl-propyl)-benzene-sulfonyl-ethylurethane (prepared from p-(y-fl-naphthoyl-pmpyl)-benzene-sulfonarnideand ethyl chloroformate in acetone in the presence of potassiumcarbonate; M.P. 79 0.; yield 68% of theory) in 200 ml. toluene and 50ml. dimethyl formamide were gently boiled for 1 hour with 2.4 g.cyclohexylamine. The reaction mixture Was Worked up in a manneranalogous to that described in Example 11 and yielded 9.4 g. (81.7% oftheory) N -[p-(y-fimaphthoylpropyl)-benzene-sulfonyl]-N -cyclohexyl ureahaving a melting point of 202 C.

In an analogous manner, there were obtained, using 8.2 g. of theabove-mentioned sulfonyl-urethane and 2.26 g.trans-4-methyl-cyclohexylamine, N-[p-(y-fl-naphthoylpropyl)-benzene-sulfonyl]-N (4 methylcyclohexyl)urea. Yield 78% of theory; M.P. 186187 C.

The p-(y-fl-naphthoyl propyl)-benzene sulfonamide required as startingmaterial was prepared in the following manner:

Naphthalene was first reacted in boiling carbon disulfide withp-nitrophenyl-butyric acid chloride by a Friedel- Crafts reactionproducing p-('y-fl-naphthoyl-propyl)-nitrobenzene (M.P. 129-130 C.;yield 66% of theory). Thereafter the nitro group was reduced withstannous chloride and alcoholic hydrochloric acid giving thecorresponding amine (M.P. 123 C.; yield 98% of theory) from which therewas prepared the corresponding sulfonyl chloride by a Meerwein-Sandmeyerreaction. The sulfonyl chloride was converted into the desiredsulfonamide by reaction with ammonia (M.P. 209-210 C.; yield 62.7% oftheory).

EXAMPLE 13 N p- 'y-o-methoxy-benzoyl-propyl) -benzene-sulfonyl]- N-(4-methyl-cyclohexyl -urea 5 g.p-('y-o-methoxy-benzoyl-propyl)-benzene-sulfonylethyl urethane in 100ml. toluene and 20 ml. dimethyl formamide were mixed with 1.3 g.trans-4-methyl-cyclohexylamine and the solution obtained gently boiledfor 1 hour. The reaction mixture was worked up in a manner analogous tothat described in Example 11 and yielded after recrystallization fromethanol 4.1 g. N -[p('y-omethoxy benzoyl propyl) benzene-sulf0nyl]-N-(4- methyl-cyclohexyl)-urea of melting point 184-185 C.

EXAMPLE l4 N -[p-('y-u-naphthoyl-propyl)-benzene-sulfonyl]-Ncyclohexyl-urea 10 g. p-('y-wnaphthoyl-propyl)-benzene-sulfonyl-ethylurethane (prepared from p-(v-a-naphthoyl-propyl)-ben- Zena-sulfonamideand ethyl chloroformate in acetone in the presence of potassiumcarbonate; M.P. 54 C.; yield 68% of theory) in 200 ml. toluene and 50ml. dimethyl formamide were gently boiled for 1 hour with 2.4 g.cyclohexylamine. The reaction mixture was worked up in a manneranalogous to that described in Example 11 and yielded 7.6 g. (67% oftheory) N -[p('y-u-naphthoylpropyl)-benzene-sulfonyl]-N -cyclohexyl ureahaving a melting point of -191 C.

The p-(v-a-naphthoyl propyl) benzene-sulfonamide required as startingmaterial was prepared in the followmg manner:

Naphthalene was first reacted in carbon disulfide at 0 C. withp-nitrophenyl-butyric acid chloride by a Friedel-Crafts reaction to givep(' -u-naphthoyl-propyl)-nitrobenzene (yield 57% of theory). Thereafterthe nitro group was reduced with stannous chloride and alcoholichydrochloric acid giving the corresponding amine (yield 74% of theory)from which there was prepared the correspondmg sulfonyl chloride by aMeerwein-Sandmeyer reaction.

9 The sulfonyl chloride was converted into the desired sulfonamide byreaction with ammonia (M.P. l02l03 C.; yield 65% of theory).

The compounds of this invention are active when administered orally orparenterally. For therapeutic use in order to ensure proper absorptionand favorable therapeutic eifect, they are preferably incorporated insuitable pharmaceutical carriers. In clinical use of these com pounds,the recommended dosage is 50800 mg, preferably 100-4OO mg. of activedrug, 2 to 4 times per day. Thus, in preparing tablets, capsules,elixirs or other dosage forms with pharmaceutical carriers, theformulation should preferably contain 100-400 mg. active drug per dosageunit.

The antidiabetic activity of the compounds of the invention was comparedwith that of certain of the, popularly known sulfonyl ureas. Thethreshold dose toxicity (LD and relative blood sugar reducing activity(N sulfanilyl-N -(n-butyl)-urea=1) were determined for the followingcompounds:

(l) N -[p-(y-benzoyl-propyl) benzene sulfonyl]-N l-methylcyclohexyl)-urea (2) N -[p-(y-benzoyl-propyl) benzene sulfonyH-N(4-methoxy-cyclohexyl -urea (3) N -[p-( -benzoyl propyl) benzenesulfonyl1- N -cyclohexyl-urea (4) N -[sulfonyl]-N -(n-butyl)-urea (5) N-(p-toluyl sulfonyl)-N -(n-butyl)-urea (6) N -(p-chloro-benzoylsulfonyl) N, propyl-urea- (chloropropamide) TABLE Compound Thresholddose Relative blood LD50 p.o. Mouse N 0. rabbit, Lv. sugar activity,i.v. (g./kg.)

We claim: 1. A member of the group consisting of benzene-sulfonyl ureasof the formula:

in which A is a member selected from the group consisting of loweralkyl, naphthyl, phenyl and substituted phenyl, wherein said substituentis a member selected from the group consisting of lower alkyl, loweralkoxy and chloro, X is a divalent aliphatic radical having 2-4 carbonatoms, and R is a member selected from the group consisting oftetrahydrothiapyranyl, cycloalkyl having 6 to carbon atoms andsubstituted cycloalkyl having 6 to 8 carbon atoms, wherein saidsubstituent is a member selected from the group consisting of loweralkyl and lower alkoxy, and the therapeutically useful alkali saltsthereof.

2. N -[p-( -benzoyl-propyl) benzene sulfonyl]-N(4-methyl-cyclohexyl)-urea.

3. N -[p-(y-benzoyl propyl) benzene sulfonyl]- N -(4-methoxy-cyclohexyl)-urea.

4. N -[p-(' -benzoyl propyl) benzene sulfonyl]- N cyclohexyl-urea.

" JOHN D. RANDOLPH, Primary Examiner.

US. Cl. X.R.

